Benzodiazonine derivatives binding to cholecystokinin or gastrin receptors

Abstract

Compounds of the formula wherein one of U and V is --CHR 2 --, and the other of U and V is selected from --N(COR 4 )--, --CH(COR 4 )--, --N(SO 2 R 4 )-- and --CH(SO 2 R 4 )--, and pharmaceutically acceptable salts thereof are ligands at gastrin and/or cholecystokinin receptors.

We claim: 
     
       1. A compound of the formula ##STR10## wherein one of U and V is --CHR 2  --, and the other of U and V is selected from the group consisting of --N(COR 4 )--, --CH(COR 4 )--, --N(SO 2  R 4 )-- and --CH(SO 2  R 4 )--, in which: R 2  is H, --COOR 5  wherein R 5  is H or C 1  to C 4  hydrocarbyl, --CONR 6  R 7  wherein R 6  is H or methyl and R 7  is aryl, substituted aryl, or a group of the formula --(C 1  to C 4 )alkylene-W, in which W is amidino, hydroxy, acyloxy, sulphamoyl, hydroxysulphonyl, carboxy, esterified carboxy, amidated carboxy, tetrazolyl, hydroxamyl, R 14  --SO 2  --NH--, R 14  --SO 2  --NH--CO--, R 14  --SO 2  --, R 14  --SO--, R 14  --CO--, R 14  --CO--NH--, R 14  --CO--NH--SO--, R 14  --CO--NH--SO 2  --, or R 15  --NH--SO 2  -- wherein R 14  is selected from the group consisting of H, C 1  to C 6  alkyl, C 1  to C 6  haloalkyl, aryl and substituted aryl, except that R 14  may not be H when attached to a sulphur atom, and R 15  is H, C 1  to C 6  alkyl, C 1  to C 6  haloalkyl, aryl, substituted aryl, --OH or --CN; or R 6  and R 7  together form a carboxy-substituted propylene, butylene or pentylene group or --COR 7  ; and R 4  is H, C 1  to C 6  hydrocarbyl in which up to three of the carbon atoms may be replaced by a nitrogen, oxygen or sulphur atom, provided that R 4  does not contain a --O--O-- group, or R 4  is a group of the formula --Q--R 16  wherein Q is selected from the group consisting of a bond, --NR 7  -- in which R 17  is H or C 1  to C 3  alkyl and --O--, and R 16  is aryl, substituted aryl, arylalkyl or (substituted aryl)alkyl;   R is independently C 1  to C 3  alkyl,   R 1  is H or C 1  to C 15  hydrocarbyl wherein one or more hydrogen atoms may be replaced by halogen atoms, and one carbon atom may be replaced by a nitrogen, oxygen or sulphur atom;   R 3  is independently halo, alkyl, --NO 2 , --NH 2  or --NHCOR 5  ;   X is H, and Y is H or C 1  to C 10  hydrocarbyl wherein one or more hydrogen atoms may be replaced by halogen atoms, and one carbon atom may be replaced by a nitrogen, oxygen or sulphur atom; or X and Y together are ═O or ═CH 2  ;   Z is: H; C 1  to C 15  hydrocarbyl, in which one or more hydrogen atoms may be replaced by a halogen atom, and up to three of the carbon atoms may be replaced by a nitrogen, oxygen or sulphur atom, provided that Z does not contain a --O--O-- group; or --(CHR 18 ) m  --R 8 , wherein R 18  is H or C 1  to C 3  alkyl and R 8  is phenyl, substituted phenyl or a group of the formula --COOR 9  or --CONR 9  R 10 , in which R 9  and R 10  are independently H or C 1  to C 6  alkyl, or R 9  and R 10  together form a propylene, butylene, pentylene or hexylene group; m is 1, 2 or 3; and   n and p are independently from 0, 1, 2, or 3, or a pharmaceutically acceptable salt thereof.     
     
     
       2. A compound according to claim 1 in which U is --CHR 2  -- and V is --N(COR 4 )--. 
     
     
       3. A compound according to claim 1, wherein R 1  is H, C 1  to C 6  alkyl- or cycloalkyl-(C 1  to C 6 )alkyl. 
     
     
       4. A compound according to claim 3 wherein R 1  is t-butyl or (1-adamantyl)methyl. 
     
     
       5. A compound according to claim 1, wherein R 4  is selected from the group consisting of H, methyl, methoxy, carboxymethyl, carboxyethyl, benzyloxy and a group of the formula --NH--Ar, wherein Ar is an aromatic group selected from the group consisting of methylphenyl, carboxyphenyl, dicarboxyphenyl, dichlorophenyl, naphthyl and indolyl. 
     
     
       6. A compound according to claim 1, wherein R 8  is selected from the group consisting of t-butyloxycarbonyl, ethoxycarbonyl, pyrrolidinyl, phenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-chlorophenyl, 4-chlorophenyl and 3-aminophenyl. 
     
     
       7. A compound according to claim 1, wherein X and Y together form a ═O group. 
     
     
       8. A compound according to claim 1, wherein n is 0. 
     
     
       9. A compound according to claim 1, wherein p is 0. 
     
     
       10. A pharmaceutical composition comprising a compound according to claim 1, together with a pharmaceutically acceptable excipient or carrier. 
     
     
       11. A method of preparing a compound according to claim 1, comprising the step of oxidising a compound of the formula ##STR11## wherein U 1  and V 1  are U and V, respectively, or protected derivatives thereof, with an oxidant to form a compound of the formula ##STR12## 
     
     
       12. A method of preparing a compound according to claim 1, in which X is H and Y is --OH, said method comprising reducing a compound of the formula wherein U 1  and V 1  are U and V, respectively, or protected derivatives thereof. 
     
     
       13. A method of preparing a compound according to claim 1, in which X is H and Y is --CH 3 , said method comprising reducing a compound of the formula ##STR13## wherein U 1  and V 1  are U and V, respectively, or suitably protected derivatives thereof. 
     
     
       14. A method of preparing a compound according to formula I above, said method comprising the step of reacting a compound of the formula ##STR14## with an isocyanate of the formula R 16  NCO or a carboxyfic acid of the formula R 1  COOH, wherein R 1' , R 2' , R 3' , R', and Z' are R 1 , R 2 , R 3 , R, and Z, respectively, or protected derivatives thereof, and U 1  and V 1  are U and V, respectively, or suitably protected derivatives thereof.   
     
     
       15. A method of preparing a compound according to claim 1, said method comprising the step of ring closure of a compound of the formula ##STR15## with a base, wherein Q 1  is H or a protecting group, and OL is a suitable leaving group. 
     
     
       16. A method of lowering gastrin or cholecystokinin activity in a patient, comprising administering to said patient an effective amount of a compound according to claim 1. 
     
     
       17. A method of preparing a compound according to claim 1, wherein X and Y together form a methylene group, said method comprising the step of reacting a compound of formula ##STR16## wherein U 1  and V 1  represent any of the groups recited in claim 1 for U and V, respectively, or protected derivatives thereof, with μ-chloro-μ-methylene-{bis(cyclopentadienyl)titanium}- dimethylaluminium. 
     
     
       18. A compound of the formula ##STR17## wherein U is --CHR 2  --, V is selected from the group consisting of --N(COR 4 )--, --CH(COR 4 )--, --N(SO 2  R 4 )-- and --CH(SO 2  R 4 )--, in which: R 2  is H, --COOR 5  wherein R 5  is H or C 1  to C 4  hydrocarbyl, --CONR 6  R 7  wherein R 6  is H or methyl and R 7  is aryl, substituted aryl, or a group of the formula --(C 1  to C 4 )alkylene-W, in which W is amidino, hydroxy, acyloxy, sulphamoyl, hydroxysulphonyl, carboxy, esterified carboxy, amidated carboxy, tetrazolyl, hydroxamyl, R 14  --SO 2  --NH--, R 14  --SO 2  --NH--CO--, R 14  --SO 2  --, R 14  --SO--, R 14  --CO--, R 14  --CO--NH--, R 14  --CO--NH--SO--, R 14  --CO--NH--SO 2  --, or R 15  --NH--SO 2  -- wherein R 14  is selected from the group consisting of H, C 1  to C 6  alkyl, C 1  to C 6  haloalkyl, aryl and substituted aryl, except that R 14  may not be H when attached to a sulphur atom, and R 15  is H, C 1  to C 6  alkyl, C 1  to C 6  haloalkyl, aryl, substituted aryl, --OH or --CN; or R 6  and R 7  together form a carboxy-substituted propylene, butylene or pentylene group or --COR 7  ; and   R 4  is H, C 1  to C 6  hydrocarbyl in which up to three of the carbon atoms may be replaced by a nitrogen, oxygen or sulphur atom, provided that R 4  does not contain a --O-- group, or R 4  is a group of the formula --Q--R 16  wherein Q is selected from the group consisting of a bond, --NR 7  -- in which R 17  is H or C 1  to C 3  alkyl and --O--, and R 16  is aryl, substituted aryl, arylalkyl or (substituted aryl)alkyl;   R is independently C 1  to C 3  alkyl,   R 1  is H or C 1  to C 15  hydrocarbyl wherein one or more hydrogen atoms may be replaced by halogen atoms, and one carbon atom may be replaced by a nitrogen, oxygen or sulphur atom;   R 3  is independently halo, alkyl, alkoxy, --NO 2 , --NH 2  or --NHCOR 5  ;   X is H, and Y is H or C 1  to C 10  hydrocarbyl wherein one or more hydrogen atoms may be replaced by halogen atoms, and one carbon atom may be replaced by a nitrogen, oxygen or sulphur atom; or X and Y together are ═O or ═CH 2  ;   Z is: H; C 1  to C 15  hydrocarbyl, in which one or more hydrogen atoms may be replaced by a halogen atom, and up to three of the carbon atoms may be replaced by a nitrogen, oxygen or sulphur atom, provided that Z does not contain a --O--O-- group; or --(CHR 18 ) m  --R 8 , wherein R 18  is H or C 1  to C 3  alkyl and R 8  is phenyl, substituted phenyl or a group of the formula --COOR 9  or --CONR 9  R 10 , in which R 9  and R 10  are independently H or C 1  to C 6  alkyl, or R 9  and R 10  together form a propylene, butylene, pentylene or hexylene group;   m is 1, 2 or 3; and   n and p are independently from 0, 1, 2, or 3, or a pharmaceutically acceptable salt thereof.     
     
     
       19. A compound according to claim 18, wherein V is --N(COR 4 )--. 
     
     
       20. A compound according to claim 18, wherein R 1  is H, C 1  to C 6  alkyl- or cycloalkyl-(C 1  to C 6 )alkyl-. 
     
     
       21. A compound according to claim 20, wherein R 1  is t-butyl or (1-adamantyl)methyl. 
     
     
       22. A compound according to claim 18, wherein R 4  is selected from the group consisting of H, methyl, methoxy, carboxymethyl, carboxyethyl, benzyloxy and a group of the formula --NH--Ar, wherein Ar is an aromatic group selected from the group consisting of methylphenyl, carboxyphenyl, dicarboxyphenyl, dichlorophenyl, naphthyl and indolyl. 
     
     
       23. A compound according to claim 18, wherein R 8  is selected from the group consisting of t-butyloxycarbonyl, ethoxycarbonyl, pyrrolidinyl, phenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-chlorophenyl, 4-chlorophenyl and 3-aminophenyl. 
     
     
       24. A compound according to claim 18, wherein X and Y together form a ═O group. 
     
     
       25. A compound according to claim 18, wherein n is 0. 
     
     
       26. A compound according to claim 18, wherein p is 0. 
     
     
       27. A pharmaceutical composition comprising a compound according to claim 18, together with a pharmaceutically acceptable excipient or carrier. 
     
     
       28. A method of preparing a compound according to claim 18, comprising the step of oxidising a compound of the formula ##STR18## wherein U 1  and V 1  are U and V, respectively, or protected derivatives thereof with an oxidant to form a compound of the formula ##STR19## 
     
     
       29. A method of preparing a compound according to claim 18, in which X is H and Y is --OH, said method comprising reducing a compound of the formula wherein U 1  and V 1  and U and V, respectively, or protected derivatives thereof. 
     
     
       30. A method of preparing a compound according to claim 18, in which X is H and Y is --CH 3 , said method comprising reducing a compound of the formula ##STR20## wherein U 1  and V 1  are U and V, respectively, or protected derivatives thereof. 
     
     
       31. A method of preparing a compound according to claim 18, said method comprising the step of reacting a compound of the formula ##STR21## with an isocyanate of the formula R 16  NCO or a carboxylic acid of the formula R 1  COOH, wherein R 1' , R 2' , R 3' , R', and Z' are R 1 , R 2 , R 3 , R, and Z, respectively, or protected derivatives thereof, and U 1  and V 1  are U and V, respectively, or suitably protected derivatives thereof.   
     
     
       32. A method of preparing a compound according to claim 18, said method comprising the step of ring closure of a compound of the formula ##STR22## with a base, wherein Q 1  is H or a protecting group, and OL is a leaving group. 
     
     
       33. A method of treating a patient suffering from a condition in which lowered gastrin or cholecystokinin activity is desirable, comprising administering to said patient an effective amount of a compound according to claim 18. 
     
     
       34. A method of preparing a compound according to claim 18, wherein X and Y together form a methylene group, said method comprising the step of reacting a compound of formula ##STR23## wherein U 1  and V 1  represents any of the groups recited in claim 18 for U and V, respectively, or protected derivatives thereof, with μ-chloro-μ-methylene-{bis(cyclopentadienyl)titanium}-dimethylaluminium.